Proteinuria - Differential Diagnosis and Investigation

• Microalbuminuria is protein between 30 and 300 mg per 24 hours. This may occur with diabetes and is discussed in its own article. Standard dip sticks will show negative with microalbuminuria.
• Bence Jones protein, as may occur with multiple myeloma, may also be undetectable on standard dipstick testing. These are the light chains of immunoglobulins.
• Albuminuria is often taken as synonymous with proteinuria:
  • Although plasma contains both albumin and globulin, the latter is much less likely to appear in the urine.
  • If the filtration system of the glomeruli may be seen as like a sieve or a mesh, then small holes or tears will permit larger particles than usual to pass through.
  • These will be the smaller rather than the larger of the particles usually held back, unless damage is severe.
  • Hence, under normal conditions, small molecules such as glucose and amino acids will pass, but not protein.
  • With mild or moderate damage, smaller proteins such as albumin will pass and only with severe damage will globulins pass.
  • Recent work also demonstrates the significance of defective albumin resorption in causing albuminuria - not purely increased permeability.¹
  • Proteinuria is usually albuminuria, but if globulin is lost too, there is serious pathology in the glomeruli.

Symptoms

Proteinuria is usually asymptomatic, although patients may complain of some "frothiness" of their urine.

Heavy and persistent proteinuria results in hypo-albuminaemia. This may produce ankle swelling, abdominal pain and breathlessness.

Signs

Patients with asymptomatic proteinuria usually have no signs, but in more severe cases (such as with nephrotic syndrome) there may be oedema, ascites , hydroceles and pleural effusions as a result of decreased oncotic pressure. The nephrotic syndrome consists of proteinuria, hypoalbuminaemia and oedema.

The following may all produce proteinuria and should be excluded:

• Fever
• Urinary tract infection
• Exercise induced proteinuria
• Orthostatic proteinuria - protein absent in an early morning sample, uncommon over the age of 30 and benign²
• In pregnancy, especially late pregnancy, pre-eclampsia must be considered
• Contamination from vaginal discharge

Urinary dipstick testing can be suggestive of a urinary tract infection, but should not be regarded as diagnostic.³

At least 3 samples of urine should be checked by stick testing to confirm the persistence of the proteinuria. It provides a crude estimation of protein concentration as follows:⁴

• Trace = 5-20 mg/dL
• 1+ = 30 mg/dL
• 2+ = 100 mg/dL
• 3+ = 300 mg/dL
• 4+ = Greater than 2000 mg/dL

Initial investigations should then include the following:

• Assess the history with special reference to drug history, family history, past medical history and occupational history.
• Blood pressure must be recorded. Several readings over time may give a more accurate picture.
• Blood tests for renal function include U&E and creatinine.
• Check for diabetes mellitus with fasting blood glucose.
• Check fasting cholesterol as this is also elevated in nephrotic syndrome.
• Check MSU for culture and microscopy. The latter is for casts and microscopic haematuria.
• Measure the urinary ratio of protein to creatinine to give an indication of severity and to extrapolate to 24 hours loss:
  • Protein/creatinine ratio >100 mg/mmol - refer nephrology.
  • Protein/creatinine ratio >45 mg/mmol with microscopic haematuria - refer nephrology.
  • Protein/creatinine ratio at lower levels than above - manage as CKD, according to stage.

Proteinuria in excess of 3.5g per day is likely to lead to a nephrotic syndrome. This usually indicates glomerular disease.²

Diseases outside the kidney that can cause proteinuria include:

• Diabetes mellitus
• Connective tissue diseases
• Vasculitis
• Amyloidosis
• Myeloma
• Congestive cardiac failure
• Hypertension

Any associated hypertension should be treated aggressively, preferably including an ACE inhibitor or, if there are side effects, an AT2 receptor blocker.

The presence of any the following increase the likelihood of significant renal disease, and indicate that further investigations or referral to a specialist is appropriate:

• Proteinuria greater >1.5 g/day. This is roughly equivalent to a protein concentration of >700 mg/l or protein/creatinine ratio >40 mg/mmol on single samples.
• Haematuria is also present
• Raised serum creatinine and if renal function is deteriorating, investigation is urgent
• Hypertension
• History suggestive of a systemic disorder such as arthralgia or rash
• Family history of renal disease
• If the urinary ratio of protein/creatinine >45 mg/mmol with microscopic haematuria, refer to a nephrologist.⁵

Low level proteinuria

If proteinuria is <1.5g protein per day or if it is intermittent, it may be followed up at 6 to 12 monthly intervals with monitoring of:

• Blood pressure
• Urine stick testing for protein and blood
• Serum creatinine

Higher level proteinuria

If proteinuria >1.5 g a day, this is likely to need management by a specialist from the outset and further investigation may include:

• Urine microscopy
• Glomerular filtration rate
• Renal ultrasound
• Possible intravenous urography
• Serological screening for auto antibodies and complement level
• Possibly renal biopsy

The possible results of hypoalbuminaemia have been mentioned. Left undetected or untreated, proteinuria may progress to renal impairment or chronic renal failure.

Patients with proteinuria are also at risk of cardiovascular disease.

Prognosis depends on the underlying cause.

It is estimated that 20% of the patients who develop end stage renal disease in the UK are suffering from glomerulonephritis. Early recognition and management of proteinuria may result in a delay in the progression to end stage disease, or the successful treatment of the underlying disease.

Population screening for proteinuria is not recommended in any healthy, asymptomatic adult population, as 4 population-based studies have found that fewer than 1.5% of those with positive dipsticks have serious and treatable urinary tract disorders.⁶